US3592804A - N-(substituted-alpha-penicilloyl)-diamino carboxylic acids - Google Patents

N-(substituted-alpha-penicilloyl)-diamino carboxylic acids Download PDF

Info

Publication number
US3592804A
US3592804A US777178A US3592804DA US3592804A US 3592804 A US3592804 A US 3592804A US 777178 A US777178 A US 777178A US 3592804D A US3592804D A US 3592804DA US 3592804 A US3592804 A US 3592804A
Authority
US
United States
Prior art keywords
penicilloyl
lysine
benzyl
acetyl
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US777178A
Other languages
English (en)
Inventor
Peter Quitt
Karl Vogler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Application granted granted Critical
Publication of US3592804A publication Critical patent/US3592804A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Penicilloic acid derivatives of the formula RINHCHC O OH (I) wherein n is an integer from 2 to 4 and R in preferred embodiments is benzyl, phenoxymethyl or allylthiomethyl and R is hydrogen or lower acyl and methods for their preparation are disclosed. These penicilloic acid derivatives are useful for inhibiting allergic reactions which occur on administration of penicillins.
  • the present invention is concerned with penicilloic acid derivatives of the general formula Preferred embodiments of the present invention relating to compounds of Formula I above are obtained when substituent R is benzyl, u-aminobenzyl, phenoxymethyl, a-phenoxyethyl, 2,6 dimethoxyphenyl, 2 ethoxy-lnaphthyl and 3-(Z-chlorophenyl)-5-methyl4-isoxazolyl.
  • a preferred group of compounds of Formula I is obtained when n has a value of 2 to 4 and the aminocarboxylic acid component is present in the L-form.
  • the compounds of Formula I can also exist as salts, most preferably as pharmaceutically acceptable salts.
  • representative salts include organic amino salts, e.g., the bis-benzylammonium and. bis-dicyclohexylammonium salts or mineral salts, such as, for example, the sodium, potassium or calcium salts.
  • Compounds of Formula I in the form of a non-pharmaceutically acceptable salt may readily be converted into the form of a pharmaceutically acceptable salt by ion exchange procedures well known in the art.
  • the compounds of the present invention corresponding to Formula I are prepared by reacting a compound of the general formula with a diaminocarboxylic acid derivative of the general formula NHZ (III) wherein n is as above and R is lower acyl or an aminoprotecting group.
  • R is an amino-protecting group and is thus contained in the reaction product, it is desired that this group be split off subsequent to the reaction and, if desired, the reaction product may be converted into a salt by procedures known in the art.
  • the reaction of compounds of Formula II With compounds of Formula III above may be conveniently undertaken in an aqueous-alkaline medium.
  • the reaction temperature is preferably in the range of from about 5 to about 30 C.
  • the compounds of Formula III can exist in optically active form or as the racemate.
  • a diaminocarboxylic acid derivative belonging to the L- series be employed.
  • a compound of Formula III in which R represents an amino-protecting group.
  • the protecting group is split off after reaction with the compound of Formula II has been effected.
  • Suitable amino-protecting groups are those known per se from peptide chemistry, for example, the tert.-butyloxycarbonyl group or the benzyloxycarbonyl group.
  • the cleavage of the protecting groups can be effected in the manner known per se.
  • a tert-butyloxycarbonyl group can, for example, be removed by means of trifluoroacetic acid.
  • the benzyloxycarbonyl group can be cleaved by means of catalytic hydrogenation.
  • the starting materials for the process in accordance with the present invention can, insofar as they are not known, be manufactured in the manner known per se.
  • Compounds of Formula I above are useful for inhibiting allergic reactions which occur on administration of penicillins.
  • the compounds of Formula I as indicated are useful as inhibitors of allergic reactions which occur on administration of penicillins.
  • These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration. They can be administered in conventional pharmaceutical forms, preferably parenterally, for example, solutions, suspensions or emulsions.
  • the pharmaceutical composition containing compounds of this invention can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for the adjustment of osmotic pressure, or buffers.
  • the compositions can also contain other therapeutically active materials.
  • a suitable pharmaceutical dosage unit can contain from about 50 mg. to about 500 mg. of the aforesaid compounds of Formula 1.
  • Suitable parenteral dosage regimens in warm-blooded mammals comprise from about 1 mg./kg. per day to about 10 mg./kg. per day.
  • the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only in that they do not, to any extent, limit the scope or practice of this invention.
  • EXAMPLE 2 87 g. of N -formyl-L-lysine were dissolved in 400 ml. of Water, treated with 186 g. of benzylpenicillin potassium salt and immediately afterwards with 500 ml. of 1 N sodium hydroxide solution, and stirred for 10 minutes with cooling, so that the temperature remained between 15 and 20. A mixture of 3 liters of ethyl acetate and 300 ml. of methanol and simultaneously 500 ml. of 3 N sulfuric acid were thereafter added. The mixture was stirred for a further 5 minutes and the aqueous phase separated off.
  • This calcium salt can also be obtained from the acid obtained as the crude evaporation residue in the first paragraph of this example in isopropanol/water by means of the addition of molar amounts of calcium acetate or calcium hydroxide.
  • EXAMPLE 9 Dry ampoules containing 100 mg. of N -(benzyl-apenicilloyl)-N -formyl-L-lysine calcium salt are prepared by conventional techniques. Prior to use, 1-5 ml. of water R -NH-OH-GOOH wherein n is an integer in the range of from 2 to 4, R is 2-pentenyl, n-pentyl, n-heptyl, allythiomethyl, 5-amino- S-carboxypentyl, benzyl, carboxybenzyl, a-aminobenzyl,
  • phenoxybenzyl phenoxymethyl, u-phenoxyet-hyl, a-phenoxypropyl, 2,6-dimethoxyphenyl, 2-ethoxy-l-naphthy1, 3- carboxy-Z-quinoxalinyl, 5-methyl-3-phenyl-4-isoaxazolyl, 3 (2 chlorophenyl)-5-rnethyl-4-isoxazolyl or 3-(2,6-dichlorophenyl)-5-metl1yl-4-isoxazolyl; and R is hydrogen or lower alkanoyl and pharmaceutically acceptable salts thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US777178A 1968-01-04 1968-11-19 N-(substituted-alpha-penicilloyl)-diamino carboxylic acids Expired - Lifetime US3592804A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH8868A CH500222A (de) 1968-01-04 1968-01-04 Verfahren zur Herstellung von Penicilloinsäurederivaten

Publications (1)

Publication Number Publication Date
US3592804A true US3592804A (en) 1971-07-13

Family

ID=4178980

Family Applications (1)

Application Number Title Priority Date Filing Date
US777178A Expired - Lifetime US3592804A (en) 1968-01-04 1968-11-19 N-(substituted-alpha-penicilloyl)-diamino carboxylic acids

Country Status (12)

Country Link
US (1) US3592804A (en, 2012)
BE (1) BE726426A (en, 2012)
CA (1) CA948636A (en, 2012)
CH (1) CH500222A (en, 2012)
DE (1) DE1815396B2 (en, 2012)
DK (1) DK125250B (en, 2012)
FR (1) FR2000020A1 (en, 2012)
GB (1) GB1201977A (en, 2012)
IE (1) IE32859B1 (en, 2012)
IL (1) IL31169A (en, 2012)
NL (1) NL159663B (en, 2012)
SE (1) SE386674B (en, 2012)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3867365A (en) * 1970-08-05 1975-02-18 Kremers Urban Co Penicilloyl-polylysine conjugates having dextro-rotary optical activity, and methods for their preparation and use
US4168263A (en) * 1976-09-28 1979-09-18 Hoffmann-La Roche Inc. Polypeptide derivatives
US4183910A (en) * 1978-04-20 1980-01-15 Levine Bernard B Method for testing to predict and/or diagnose allergy to penicillins, and compounds and compositions for use in such tests
US4228147A (en) * 1979-05-09 1980-10-14 Levine Bernard B Composition and method for testing to predict and/or diagnose allergy to penicillins
FR2464258A1 (fr) * 1979-08-30 1981-03-06 Levine Bernard Nouveaux derives d'amine et d'aminoacide de penicilline et compositions les contenant, permettant de predire et/ou diagnostiquer une allergie aux penicillines

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3867365A (en) * 1970-08-05 1975-02-18 Kremers Urban Co Penicilloyl-polylysine conjugates having dextro-rotary optical activity, and methods for their preparation and use
US4168263A (en) * 1976-09-28 1979-09-18 Hoffmann-La Roche Inc. Polypeptide derivatives
US4183910A (en) * 1978-04-20 1980-01-15 Levine Bernard B Method for testing to predict and/or diagnose allergy to penicillins, and compounds and compositions for use in such tests
US4228147A (en) * 1979-05-09 1980-10-14 Levine Bernard B Composition and method for testing to predict and/or diagnose allergy to penicillins
FR2464258A1 (fr) * 1979-08-30 1981-03-06 Levine Bernard Nouveaux derives d'amine et d'aminoacide de penicilline et compositions les contenant, permettant de predire et/ou diagnostiquer une allergie aux penicillines

Also Published As

Publication number Publication date
GB1201977A (en) 1970-08-12
FR2000020A1 (en, 2012) 1969-08-29
DE1815396B2 (de) 1977-10-13
DE1815396C3 (en, 2012) 1978-06-08
NL6816294A (en, 2012) 1969-07-08
CH500222A (de) 1970-12-15
NL159663B (nl) 1979-03-15
IE32859L (en) 1969-07-04
SE386674B (sv) 1976-08-16
CA948636A (en) 1974-06-04
IE32859B1 (en) 1973-12-28
IL31169A (en) 1972-11-28
DK125250B (da) 1973-01-22
IL31169A0 (en) 1969-01-29
BE726426A (en, 2012) 1969-07-03
DE1815396A1 (de) 1970-01-08

Similar Documents

Publication Publication Date Title
EP0184550B1 (de) 5-Amino-4-hydroxyvalerylamid-Derivate
KR900007241B1 (ko) 2환성 아미노산 유도체의 제조방법
KR910000234B1 (ko) 시스, 엔도-2-아자비사이클로[5.3.0]데칸-3-카복실산 유도체의 제조방법
KR100312539B1 (ko) 피페라진유도체
US20230322668A1 (en) Protease inhibitors as antivirals
JPS6120544B2 (en, 2012)
GB2143528A (en) Salts of 2-(2,6-dichloroanilino)-phenyl acetic acid
RU2107062C1 (ru) N-замещенные производные имидазола или их соли, способ их получения, промежуточное соединение и фармацевтическая композиция, являющаяся антагонистом ангиотенсина ii
JPH0587504B2 (en, 2012)
JPH0346463B2 (en, 2012)
HU209413B (en) Method for producing 2-azabicyclo [3.1.0] hexane-3-carboxylic acid derivatives as well as their physiologically acceptable salts
US4311706A (en) Novel dopa/dopamine prodrugs
EP0236734A2 (de) Durch schwefelhaltigen Gruppen substituierte 5-Amino-4-hydroxyvalerylderivate
JPS59163356A (ja) Ｎ−フエニルベンズアミド誘導体ならびにその製造法および応用
JPS6143193A (ja) ホスフアチジル化合物及びその製造方法並びにこの化合物を含有する医薬
HU186983B (en) Process for preparing new 3-amino-5-pregnene derivatives and salts thereof
CS200513B2 (en) Process for preparing omega-aminoacylamidic compounds
EP0374098A2 (de) Retrovirale Proteasehemmer
JPH05222005A (ja) ３（ｓ）−アミノ−４−シクロヘキシル−２（ｒ）−ヒドロキシ酪酸若しくは４−シクロヘキシル−（２ｒ，３ｓ）−ジヒドロキシ酪酸又は関連類似体を含む環状レニン阻害剤
US3592804A (en) N-(substituted-alpha-penicilloyl)-diamino carboxylic acids
JPH04230698A (ja) 酸化型グルタチオンアルキルエステル
JPH0559105B2 (en, 2012)
US5082836A (en) Compositions and methods of use of cyclic sulfur-containing compounds
JP3891503B2 (ja) 製薬学的に活性なβ−アミノ酸類の許容性の改善
AU672867B2 (en) 4-amino-3-hydroxycarboxylic acid and their use as anitvirals